Multiple myeloma (MM) is the second most common hematological malignancy in the United States where it accounts for about 11,000 deaths annually. MM remains an incurable disease, and nearly all MM patients will eventually relapse and develop resistance to currently available agents including newer proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide). There is an unmet medical need for the development of novel therapeutic agents that do not share similar mechanism of action with these agents. Sphingolipid metabolism is increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinase 2 (SK2) provide a potential site for manipulation of the ceramide/sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. The research in the applicant's lab has demonstrated that SK2 is overexpressed in MM and that SK2 inhibitor (ABC294640) down-regulated c-Myc expression and inhibited myeloma growth in vitro and in vivo in myeloma xenograft mouse model. The long-term goal is to target SK2 for the treatment of MM. The overall objective in this application is to determine the mechanisms through which SK2 inhibition down-regulates c-Myc expression and to further define the roles of SK2 in MM development and progression. The central hypothesis is that SK2 provides an important therapeutic target for the treatment of MM. The rationale for the proposed research is that these studies will contribute a missing, fundamental element of knowledge to the roles of SK2 in MM pathogenesis and establish critical safety profile, maximal tolerated dose, pharmacokinetics and pharmacodynamics data of ABC294640 in myeloma patients. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) determine the mechanisms and the role of c-Myc down-regulation in ABC294640-mediated myeloma cell death); 2) define the roles of SK2 in myeloma disease pathogenesis and progression; and 3) perform a phase Ib clinical trial testing the safety of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients. Under the first aim, the role of c-Myc down regulation in ABC294640-mediated killing and the mechanism through which ABC294640 down-regulates c-Myc will be determined. Under the second aim, the role of SK2 in myeloma development will be investigated using myeloma mouse model and intravital imaging. Under the third aim, a phase Ib clinical trial will be carried out and correlative studies will be performed. The approach is innovative, in the applicant's opinion, because it departs from the status quo by targeting sphingolipid metabolism pathway for the treatment of MM. A new class of therapeutic drugs for MM is expected to attain as a result. The proposed research is significant, because it is expected to vertically advance and expand the knowledge of MM pathogenesis and the treatment of MM. Such knowledge has the potential to improve the care of patients with MM, a disease with a high unmet clinical need.